海马SGK1促进抑郁易感性:早期生活逆境、压力和遗传风险的作用。

IF 10.1 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Amira Millette, Milenna T van Dijk, Irina Pokhvisneva, Yifei Li, Rory Thompson, Sachin Patel, Rosemary C Bagot, Aniko Naray-Fejes-Toth, Geza Fejes-Toth, Patricia Pelufo Silveira, Gustavo Turecki, Juan Pablo Lopez, Christoph Anacker
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引用次数: 0

摘要

抑郁症患者的血清和糖皮质激素调节激酶1 (SGK1)在糖皮质激素暴露后海马神经元和外周血中升高。然而,其在精神病理学中的机制作用及其与人脑的相关性尚不清楚。为了解决这一差距,我们研究了人类死后脑组织,发现与自然死亡的健康受试者相比,抑郁自杀者海马中的SGK1表达更高。我们观察到有早期生活逆境(ELA)的受试者中SGK1水平最高,ELA是精神疾病的主要危险因素。为了确定海马中SGK1增加的潜在遗传因素,我们对ABCD研究的大量人群样本计算了基于表达的多基因风险评分(ePRS),发现与海马高SGK1表达相关的一系列遗传变异预测抑郁严重程度,并调节ELA、抑郁症状和自杀企图之间的关联。与人脑类似,ELA、成人慢性应激和慢性皮质酮暴露的小鼠模型中,海马SGK1表达增加,海马特异性敲低SGK1赋予应激诱导的行为异常的恢复能力。为了测试SGK1作为潜在的治疗靶点,我们给小鼠注射了小分子抑制剂GSK650394,发现药物抑制可以增强应激恢复能力,增加成年海马神经发生,并挽救应激诱导的齿状回过度活跃。我们的跨物种研究结果揭示了海马SGK1在应激恢复中的新作用,强调了ELA和SGK1在抑郁和自杀风险中的相互作用,并首次确立了SGK1在应激诱导的精神病理中的功能作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Hippocampal SGK1 promotes vulnerability to depression: the role of early life adversity, stress, and genetic risk.

Serum and Glucocorticoid-regulated Kinase 1 (SGK1) is elevated in hippocampal neurons following glucocorticoid exposure and in peripheral blood of depressed patients. However, its mechanistic role in psychopathology and its relevance to the human brain are unknown. To address this gap, we investigated human postmortem brain tissue and found higher SGK1 expression in the hippocampus of depressed suicide decedents compared to healthy subjects who died of natural causes. We observed the highest levels of SGK1 in subjects with reported early life adversity (ELA) - a major risk factor for psychiatric disorders. To determine potential genetic factors underlying increased SGK1 in the hippocampus, we computed expression-based polygenic risk scores (ePRS) for a large population sample from the ABCD study and found that a collection of genetic variants associated with high hippocampal SGK1 expression predicts depression severity and moderates associations between ELA, depressive symptoms, and suicide attempts. Similar to the human brain, hippocampal SGK1 expression was increased in mouse models of ELA, adult chronic stress, and chronic corticosterone exposure, and hippocampal-specific knockdown of SGK1 conferred resilience to stress-induced behavior abnormalities. To test SGK1 as a potential therapeutic target, we injected mice with the small molecule inhibitor, GSK650394, and found that pharmacological inhibition conferred stress resilience, increased adult hippocampal neurogenesis, and rescued stress-induced dentate gyrus hyperactivity. Our cross-species findings reveal a novel role for hippocampal SGK1 in stress resilience, highlight an interaction between ELA and SGK1 on depression and suicide risk, and establish for the first time a functional role for SGK1 in stress-induced psychopathology.

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来源期刊
Molecular Psychiatry
Molecular Psychiatry 医学-精神病学
CiteScore
20.50
自引率
4.50%
发文量
459
审稿时长
4-8 weeks
期刊介绍: Molecular Psychiatry focuses on publishing research that aims to uncover the biological mechanisms behind psychiatric disorders and their treatment. The journal emphasizes studies that bridge pre-clinical and clinical research, covering cellular, molecular, integrative, clinical, imaging, and psychopharmacology levels.
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